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Tracers for monitoring the activity of sodium/glucose cotransporters in health and disease

a sodium/glucose cotransporter and glucose metabolism technology, applied in the field of radiolabeled tracers and methods for monitoring the activity of sodium/glucose cotransporters, can solve the problems of loss of consciousness and even death, poor substrate for 2-fdg glucose transporters, and genetic defects in glucose transport across the blood brain. , to achieve the effect of better assessing the usefulness (and/or the deleterious effect) of the agent on the mammal

Active Publication Date: 2010-01-14
RGT UNIV OF CALIFORNIA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0018]In a second aspect of the invention, a method of detecting the activity of a sodium / glucose cotransporter in vitro is provided, and comprises the steps of obtaining a cellular sample; administering to the cellular sample a radiolabeled tracer of the type described herein; isolating a first aliquot of the cellular sample after a predetermined time interval; assaying the first aliquot for radioactivity; and, after each of one or more additional time intervals, isolating a further aliquot of the cellular sample, and assaying it for radioactivity. Preferably, each aliquot is washed with a buffer solution prior to being assayed for radioactivity. Radiographic techniques include, without limitation, autoradiography, scintillation counting, PET (including micro-PET) and SPECT. This method can be enhanced by using it to monitor the effect on the cellular sample of one or more administered pharmacological or other agents.
[0020]In a variation of this method, a tracer that is known to be a substrate for a first SGLT (e.g., SGLT1), but not a second SGLT (e.g., SGLT2 or SGLT4) (or vice versa), is utilized, allowing one to map or probe different metabolic pathways, as well as the effect of external agents on such pathways. By also administering a pharmacological or other agent to the mammal, and monitoring its effect on SGLT activity, one can better assess the agent's usefulness (and / or its deleterious effect) on the mammal.

Problems solved by technology

Failure to supply the brain with glucose, for example in hypoglycemia, results in loss of consciousness and even death.
Children with genetic defects in glucose transport across the blood brain have severe developmental problems (IQ, motor co-ordination, infantile seizures, etc).
However, 2-FDG is a very poor substrate for these glucose transporters, and so 2-FDG PET does not measure glucose utilization into cells by the SGLTs.
This means that mannose and 2-deoxy-D-glucose are poor substrates for SGLT1 and SGLT2.
There are limitations with these probes in that the lifetime of [11C] is shorter than that of [18F] (20.4 vs.

Method used

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  • Tracers for monitoring the activity of sodium/glucose cotransporters in health and disease
  • Tracers for monitoring the activity of sodium/glucose cotransporters in health and disease
  • Tracers for monitoring the activity of sodium/glucose cotransporters in health and disease

Examples

Experimental program
Comparison scheme
Effect test

example 1

Methyl-4-deoxy-4-[18F]fluoro-alpha-D-glucopyranoside

[0063]Methyl 2,3,6-tri-O-acetyl-4-O-trifyl-alpha-D-galactopyranoside and methyl 2,3,6-tri-O-acetyl-4-O-trifyl-beta-D-galactopyranoside were prepared following the procedures described in the literature. (Kiefel M J; Beisner B; Bennett S; Holmes I D; von Itzstein M: Synthesis and biological evaluation of N-acetylneuraminic acid-based rotavirus inhibitors. Journal of Medicinal Chemistry 1996, 39, 1314-1320.)

[0064][18F]Fluoride was prepared by proton bombardment of [18O] enriched water via [18O](p,n)[18F] nuclear reaction. At the end of the bombardment, activity was transferred into a solution of 1 mg of potassium carbonate and 10 mg of Kryptofix 2.2.2 in 40 μL of water and 960 μL of acetonitrile. The volatile components were evaporated under a stream of nitrogen at 110° C. and the residual moisture was co-evaporated with acetonitrile (3×0.5 mL).

[0065]Methyl 2,3,6-tri-O-acetyl-4-O-trifyl-beta-D-galactopyranoside (5 mg) dissolved in 1 ...

example 2

Radiosynthesis of O-[11C]-Methyl-4-FDG

[0072]This procedure is a modification of the one described by Bormans et al., J. Nucl. Med 44:1075-1081 (2003) for 11C-methyl glucose. [11C]—CH3I was synthesized from [11]CO2 using standard procedures well established in the literature. [11C]-methyl triflate was obtained by passage of [11C]-CH3I over a Ag-triflate column at 180° C. [11C]-methyl triflate was bubbled through a solution of 3 mg of 4-FDG (prepared as described above) in a mixture of 0.5 mL of 0.05 mol / L NaOH and 1 mL of acetone for 5 min at room temperature. The solution was then neutralized with phosphate buffer, pH 6 (0.5 mol / L), and acetone was evaporated by careful heating under a stream of helium. The resulting solution was diluted with saline to an appropriate radioactive concentration for in vivo studies. For biodistribution of the individual alpha and beta-anomers, the anomeric mixture was separated using high-performance liquid chromatography (HPLC) with an Aminex HPX-87c...

example 3

Use of a Tracer as an In Vitro Marker of SGLTs

[0073]Procedures aimed at detecting radioactivity (e.g. autoradiography) are used to map distribution and function (e.g. pharmacological blockade) of SGLTs in individual cells, cell lines, tissue specimens, etc. Isolated tissue specimens, cells, or cell lines are incubated in media under physiological conditions of pH, temperature, and oxygenation. A radiolabeled tracer as described above is added and, at various time intervals, aliquots of the tissue / cells are removed and washed free of the tracer with ice-cold buffers. The radioactivity in the whole tissue or cell sample is assayed using a counter (e.g., a gamma or liquid scintillation counter), and the uptake (moles) at each time point is calculated (corrected for time decay and normalized for the quantity of tissue / cells used). The tracer uptake is optionally measured in the presence and absence of one or more competitive agents for SGLTs, e.g., sodium, phlorizin, glucose, galactose,...

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Abstract

Radiolabeled tracers for sodium / glucose cotransporters (SGLTs), their synthesis, and their use are provided. The tracers are methyl or ethyl pyranosides having an equatorial hydroxyl group at carbon-2 and a C1 preferred conformation, radio-labeled with 18F, 123I, or 124I, or free hexoses radiolabeled with 18F, 123I, or 124I. Also provided are in vivo and in vitro techniques for using these and other tracers as analytical and diagnostic tools to study glucose transport, in health and disease, and to evaluate therapeutic interventions.

Description

CROSS-REFERENCE TO RELATED APPLICATION[0001]This application claims the benefit of U.S. provisional application No. 60 / 683,642, filed May 23, 2005, the entire contents of which are incorporated herein by this reference.ACKNOWLEDGEMENT OF GOVERNMENT SUPPORT[0002]This application was made with government support under Grant No. DK19567 (E. Wright), awarded by the National Institutes of Health, UCLA discretionary funds (E. Wright), and DE-FC03-02ER63-420, awarded by the Department of Energy (J. Barrio). The Government has certain rights in the invention.FIELD OF THE INVENTION[0003]The present invention relates generally to tracers and methods for monitoring glucose metabolism, and more particularly to radiolabeled tracers and methods for monitoring sodium / glucose cotransporters, in vitro and in vivo.BACKGROUND OF THE INVENTION[0004]Great strides have been made over the past 25 years in the functional imaging of the human body using positron emitters (e.g., carbon-11, fluorine-18, and i...

Claims

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Application Information

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IPC IPC(8): A61K51/00C07H5/02C12Q1/02
CPCG01N33/60G01N2400/00G01N33/6872
Inventor WRIGHT, ERNEST M.BARRIO, JORGE R.HIRAYAMA, BRUCE A.KEPE, VLADIMIR
Owner RGT UNIV OF CALIFORNIA
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